Hematopoietic cells are rare, pluripotent cells, having the capacity to give rise to all lineages of blood cells. Through a process referred to as commitment, self-renewing stem cells are transformed into progenitor cells which are the precursors of several different blood cell types, including erythroblasts, myeloblasts and monocyte/macrophages. Due to their self-renewing capacity, stem cells have a wide range of potential applications in transfusion medicine, and in particular, in the autologous support of cancer patients.
Procedures have been developed whereby stem cells can be obtained from a donor, stored and later transplanted into a patient experiencing an immunosuppressive condition, such as following high dose chemotherapy or total body radiation. In the past, stem cells were harvested from bone marrow in a costly and painful procedure which required hospitalization and general anesthesia. New developments in technology, however, now make it possible to derive stem cells and committed progenitor cells from peripheral blood. Collection of stem cell products (SC products), a term which includes both true stem cells and committed progenitor cells (i.e., CD 34.sup.+ cells are included), can thus be done on an outpatient basis, eliminating the need for hospitalization. In addition, stem cell products can also be derived from peripheral blood during elective surgeries.
Once collected, the SC products, whether from bone marrow or peripheral blood, can be stored for future use, one of the most significant of which is transplantation to enhance hematologic recovery following an immunosuppressive procedure such as chemotherapy.
There is, however, one significant drawback to the use of this very beneficial reinfusion procedure. Inevitably, when SC products are obtained from a cancer patient, a significant number of tumor cells will also be collected, thereby contaminating the SC product. Subsequently, when the SC product is reinfused into the patient, the tumor cells are also reintroduced, increasing the concentration of tumor cells in the patient's blood stream. While circulating tumor cells have not been directly linked to the relapse of a particular cancer, in the case of lymphoma, for example, reinfused cells have been traced to sites of disease relapse. In cases involving adenocarcinoma, it has been estimated that for a 50 kilogram adult, approximately 150,000 tumor cells can be reinfused during a single stem cell transplantation. Moreover, it has been shown that the tumor cells present in the SC product are viable and capable of in vitro clonogenic growth, thus suggesting that they could indeed contribute to post-reinfusion relapse. Ovarian cancer cells, testicular cancer cells, breast cancer cells, multiple myeloma cells, non-Hodgkin's lymphoma cells, chronic myelogenous leukemia cells, chronic lymplocytic leukemia cells, acute myeloid leukemia cells, and acute lymphocytic leukemia cells are known to be transplantable.
The extent of tumor cell contamination of SC products appears to vary greatly from patient to patient, and values within the range of 11 to 78 percent have been recorded. Therefore, as the reinfusion of circulating tumor cells may well circumvent the benefits provided by aggressive chemotherapy followed by stem cell transplantation, the development of techniques that effectively remove tumor cells from SC products will significantly further the widespread use of a very beneficial and valuable clinical procedure.
Methods currently used to separate the valuable stem cells from the undesired tumor cell-contaminated product rely on a positive selection technique that identifies stem cells and progenitor cells that express markers for the CD34.sup.+ antigen and remove them from the contaminated product. These methods are very labor intensive and require the use of specialized equipment, thus greatly increasing the cost of patient care and severely limiting the use of SC products in transplantation procedures.
An alternative to positive selection for removal of tumor cells from blood was provided by Gudemann et al., who described filtration with special leukocyte depletion membrane filters (which work by adsorbing charged particles) to remove urologic tumor cells from autologous blood during an intraoperative mechanical autotransfusion (IAT) procedure. (Gudemann, C., Wiesel, M. and Staehler, G., Intraoperative Autotransfusion In Urologic Cancer Surgery By Using Membrane Filters, XXIII.sup.rd Congress of the ISBT, abstracts in Vox Sang., 67 (S2), 22.) A disadvantage of the membrane filters used by Gudemann el al is that they do not selectively retain tumor cells. White blood cells, including stem cells, are also retained. Thus, tumor cells are not removed from stem cells.
The work of Miller et al also teaches that standard blood transfusion filters are ineffective at removing tumor cells from autologous blood. (Miller, G. V., Ramsden, C. W. and Primrose, J. N., Autologous transfusion: an alternative to transfusion with banked blood during surgeryfor cancer, B. J. Surg. 1991, Vol. 78, Jun., 713-715).
It is therefore desirable, based upon the valuable benefits achieved by the transplantation of previously obtained stem cell products, benefits that ultimately result in increased survival rates, to provide a low-cost, clinically effective method for the selective removal of tumor cells from tumor cell-contaminated stein cell products.